Quinoline compounds and process of making same



meme July 5, 1949 oomomm oomomms AND raocsssor MAKING Joseph H. Burckhalter, Detroit, Eldon M. Jones and Albert L. Bawlins, Grouse Pointe Woods, Frank H. Tendick, Grosse Pointe Park, and Walter F. Holcomb, Detroit, Mich, ascignon to Parke, Davis & Company, Detroit, Mich, a

corporation of Michigan No Drawing. Application November 5, 1945,

Serial No. 628,906

This invention relates to the manufacture of certain new and useful quinoilne compounds having the formula,

where Z is hydrogen, halogen, CN, -COOH, --CO(lower aikyl), lower alkyl or lower alkoxy,

, n being 1, 2 or 3, R is hydrogen, halogen, OH,

or a saturated or unsaturated lower alkyi, Bi is hydrogen or a saturated alkyl radical of 110 carbon atoms inclusive and R2 is a saturated aikyl radical of 1-10 carbon atoms inclusive, Hi and R2 may be taken together with -N to form a heterocyclic ring consisting of a member of the class piperidine and morpholine, thiomorpholine and pyrrolidine.

These new compounds are useful therapeutic agents and, in general, they are characterized by their toxicity to plasmodia. These compounds may be used either in the term of their bases or their salts with organic or inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, lactic acid, tartaric acid, gluconic acid, citric acid and alkyl sulfonic acids or as the insoluble salt of methylene disalicyclic acid.

This application is a continuation-impart of our copending application. Serial No. 576,900, filed I February 8, 1945.

We have found that the compounds of this invention may be prepared by the rea tion of the primary amino group of an aminoph nol which has at least one unsubstituted position ortho or para to the phenolic hydroxyl, with a reactive halogen atom selected from theclass consisting of chlorine and bromine attached to the carbon atom in the 4 position of a quinoline compound of the formula,

9 Claims. (01. zoo-2st) thereby Iorming hydrogen halide and a 4-(hy-- d'rcxyanilino) quinollne compound 0! the general formula,

and thereafter condensing said 4-(hydroxy anilino) qulnoline with formaldehyde and an amine oi the formula,

/Ri EN or with the equivalent products of mixtures of products resulting from the first condensing said amine and formaldehyde, thereby introducing the group R1 -CHil B: into the aryl nucleus ortho or para to the phenolic hydroxyl to form a compound of the formula,

wherein Z, n, R1 and R2 have the same significance as given above and X is a chlorine or bromine atom.

The reaction of the aminophenols with the or a. phenol, the acid or phenol serves both as a catalyst-and a solvent. Some examples of the phenol which we may employ to effect this reaction are phenol, o-cresol, p-cresol, m-cresol, mixed cresols and the like. The inorganic acids which we use are, in general, mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric and like acids. Some of the solvents other than the aforementioned concentrated organic acids and phenols which we may use are water, water-water-miscible organic solvent mixtures and anhydrous water-miscible organic solvents. By water-miscible organic solvents we mean such solvents as lower allqrl alcohols such as methanol, ethanol and n-propanol, lower alkyl' ketones such as acetone and methyl ethyl ketone, and ethers such as dioxane and ethylene glycol mono-ethyl ether.

.The reaction of the 4-(hydroxyanilino) quinclines with formaldehyde and the various amines is preferably carried out in an alcoholic type solvent. Some examples of such solvents are (methanol, ethanol, n-propanoi. iso-propanol and the like. An acid addition salt of the amine such as the hydrochloride salt may be employed in the reaction instead of the free amine.

The invention is illustrated by the following examples: 1

Example 1.-4- 3 -N-piperidylmethyZ- '-hy- P drozyanilino) -7-chloroquinoltne g. of p-amiiiophenol is dissolved in 40 cc. of 2 N hydrochloric acid and 40 cc. of dioxane.

The pH of the solution is adjusted to about 4 by the addition of 10 N sodium hydroxide solution and 18.2 g. of 4,7:dichloroqulnoline added. The resulting mixture is refluxed for two hours, cooled, diluted to 600 cc. with water and made alkaline with ammonium hydroxide. The precipitated product is removed by filtration, washed well with water and allowed to dry in the air.

A mixture consisting of 10 g. of 4-(4'-hydroxyaniline)-7-chloroquinoline dissolved in absolute ethanol is treated with a solution of 3.1 g. of piperidine and 1.2 g. of formaldehyde in 25 cc. of absolute ethanol. The reaction mixture is heated under reflux for four hours, evaporated to onehalf volume and the warm solution treated with an excess of hydrogen chloride in absolute ethanol. Acetone is added until the solution becomes turbid and then the solution is cooled. The crude hydrochloride is recrystallized from absolute ethanol-ethyl acetate mixture; M. P. 301-2" C. dec.

By using an equivalent amount of a-methyl piperidine instead of piperidine in the above pro cedure one obtains 4- (3' N-a-methylpiperidylmethyl-4'-hydroxyanilino) -7-chlor.oquinoline dihydrochloride; M5: P. 286-88 C.

4 (3' N morpholinylmethyl 4' hydroxyanilino)-7-chloroquinoline dihydrochloride is obtained by using an equivalent amount of morpholine in the above procedure in place of piperidine; M. P. 292 C. dec.

Example 2.4- (3'-diethylaminomethyl-4'-hudroxyanilino) -7-chloroquinoline A (gmmcium l0 i ci \N/ 72.8 g. (0.5 mole) of p-aminophenol hydrochloride is dissolved in 500 cc. of water and added to 99 g. (0.5 mole) of 4,7-dichloroquinoline. After a few minutes of warming in a steam bath, 4 4 -hydroxyanilino 7-chloroquinoline hydrochloride, of sufflcient purity for use in further experiments, precipitates as a yellow crystalline solid. Reerystallized from methanol, the M. F. is over 300 C.

A mixture consisting of 13.5 g. of 4-(4'-l:iydroxyanilino)-7-chloroquinoline hydrochloride dissolved in absolute ethanol is treated with' a solution of 4.38 g. of .diethylamine and 1.8 g. of paraformaldehyde in cc. of absolute ethanol. The reaction mixture is heated under reflux for 16 hours, evaporated to one-half volume and the warm solution treated with an excess of hydrogen chloride dissolved in absolute ethanol. Acetone is added to the warm solution until it becomes turbid and then the solution is cooled. The crude dihydrochloride which separates is collected and purified by recrystallization from methanol; M. P. 240-2 C.

By using an equivalent amount of 4-(4'-hydroxyanilino)-7-bromoquinoline in the above procedure, 4 (3' diethylaminomethyl-4'-hydroxyanilino)-7-bromoquinoline dihydrochloride is obtained; M. P. (base) 206'-8 C. dec.

Example 3.4-(3'-ethylaminomethzll-4'-hydrozyanilmo) -7-chloroqui1zolme it v ag...

K (JHzN I C I Cent A mixture consisting of 30.7 g. (0.1 mole) of 4- (4-hydroxyanilino) -7-chloroquinoline hydrochloride (prepared as' described in Example 2), 6.3 g. (0.2 mole) of paraformaldehyde and 27.2 cc. (0.2 mole) of an alcoholic solution of ethylamine in 125 cc. of absolute alcohol is refluxed for sixteen hours. The volatile materials are removed by distillation under reduced pressure, and the residue is treated with 100 cc. of warm 2 N hydrochloric-acid. The undissolved solid is removed by filtration and the filtrate made alkaline with ammoniaand extracted withchloro- I form. The chloroform extracts are dried, filtered and then evaporated to dryness. The residue is taken up in acetone and 'an excess of dry hydrogen chloride gas passed into the solution. The precipitated dihydrochloride of the product is collected and purified by recrystallization from methanol or ethanol; M. P. 280 C. with decomposition.

By using n-propylamine in the above procedure instead of ethylamine 4-(3'-n-propylaminomethyl-4'-hydroxyanilino)-7- chloroquinoline dihydrochloride is obtained.

Example 4. ---.4-(3 di-n-butylahainomethulJ- hydroryanilino) -7-chloroquinoline HtN (CHiCHiCHiCHOi A solution of 1.8 a. of paraformaldehyde and "1.75 g. of di-n-butylamine in 20 cc. of methanol is added to a solution of 13.5 g. of 4-(4'-hydroxy aniline)-'l-chloroquinoline in methanol. The resuiting mixture is refluxed for 24 hours and then approximately one-half of the methanol distilled off. The residue is cooled and the crystalline din-butylamine one obtains i-[3-(ethyl-rir-butyl) aminomethyl-d'-hydroxyanilinol -7-chloroquino-- line dihydrochloride.

Example 5. 4-(3'-N-piperidylmethyl-4,6-dihydromyanilino) -7-chloroquinoline NH- OH CHQCE:

, (.IHzN CH5 Cl C320 2 A mixture consisting of 10 g. of ljl-dichloroquinoline and 10 g. of ZA-dihydroxyaniline hydrochloride in 200 cc. of water is refluxed for onehalf hour. The solution is cooled, diluted to 600 cc. with water and made alkaline with ammonium hydroxide. The precipitated 4-(2',4-dihydroxyanilino) '7 chloroquinoline is collected,

washed with water and dried in the air.

A solution 1.8 g. of paraformaldehyde and 4.8 g. piperidine in cc. of methanol is added to a solution of I43 g. of 4-(ZJi dihydroXyaniIino) 'l-chloroquinoline in 300 cc. of methanol and the resulting mixture refluxed for twelve hours. Approximately onehalf of the methanol is removed by distillation and the solution treated with an excess of dry hydrogen chloride. 0n standing in the refrigerator the crystalline hydrochloride of lino) -7.-chloroquinoline separates.

i-(3'-N-piperidylmethyl-4,6-dihydroxyani- The product is cooled, washed with acetone and purified by recrystallization from methanol-acetone mixture.

Example 6.-4-(3'-diethylaminomethyl 4'- hi!- drowy-5'-allylanilino) -7-chloroquinollne 7.6 g. of 3-allyl-l-hydroxyaniline is dissolved in 150 cc. of water and the pH of the solution adjusted toabout 4 by the addition of fi-N-hydro 6 chloric acid. 10 g. of 4,7-dichloroquinoline is added and the mixture refluxed for two hours. The solution is diluted to a volume of 500 cc. and the 4- (3'-allyl-4='-hydroxyanilino) -'l-chloroquinoline precipitated by the addition of ammonium hydroxide. The product is removed by filtration, washed with water and allowed to dry in the air.

15.6 g. of i-(3'-allyl-4'-hydroxyanilino)-7- chloroquinoline is dissolved in absolute methanol and the solution treated with a solution of 4.4 g. of diethylamine and 1.8 g. paraformaldehyde in 25 cc. or absolute methanol. The reaction mixture is refluxed for ten hours and then evaporated to about one-half volume. Anexcess of dry hydrogen chloride in methanol is added to the solution and the hydrochloride precipitated by the addition of anhydrous ether. Thecrude hydrochloride is treated with 300 cc. of water, so: lution made alkaline with ammonium hydroxide, and the base extractedwlth ether. The ether extracts are dried over sodium sulfate, the drying agent removed by filtration and the ether evaporated. The base is taken up in hot isopropanol and are crystallized several times from this solvent; M. P. 154-5 0.

By using piperidine instead of diethylamine in the above procedure one obtains 4-(3'-N- piperidylmethylt'-hydroxy- 5' allylanilinol -'lchloroquinoline; M. P. 189-90 C.

Example 7.--3-methyZ-4-(3n-butylaminometityZ-4'-hydromyanilino) -7-chloroquinoline IFH- on H CH1 Hm Cl N/ cnicmcmcm 11 g. of p-aminophenol is dissolved in 259 cc. of water and the pH of the solution adjusted to about 4 by the addition of concentrated hydrochloric acid. 20 g. of 3-methyl-4=,7-dichloroouin oline is added and the mixture refluxed for three hours. The solid hydrochloride of product is collected, washed with waterand dried.

A solution of 1.8 g. of paraformaldehyde and 4.3 g. of n-butylamine in 25 cc. methanol is added to 14.2 g. of B-methyli-(Q-hydroxyanilino)-'l chloroquinoline hydrochloride in 300 cc. of methanol and mixture refluxed for twenty-four hours. The volatile materials are removed by distillation under reduced pressure, and the resh due is treated with cc. of warm 2 N hydrochloric acid. The undissolved solid is removed by filtration and the filtrate made alkaline with ammonia and extracted with chloroform, The chloroform extracts are evaporated to dryness and the residue taken up in acetone. The solution is treated with an excess. of dry hydrogen chloride gas and the dihydrochloride, which separates, collected and purified by recrystalliza tion from absolute methanol.

Example 8.--3-methyl-4- (3-N-morpholinylmeth- (l l-4-hydr0$yanilino) -7-chloroquinolz'ne A solution of 4.9 g. of morpholine and .1. 8 g. of paraformaldehyde in 20 cc. of alcohol is added to Example 9.-4-i3-N-piperidylmethyl-4'-hg droxyanilino) -6-methoa:yquinoline NH- OH I omen, cmo- J c H:

\C HzCz N 10 g. of p-aminophenol is dissolved in 40 cc. of 2 N hydrochloric acid and 40 cc. of dioxane. The pHof the solution is adjusted to about 4 by the addition of 10 N sodium hydroxide solution and 17.7 g. of 4-chloro-fi-methoxyquinoline added.

The resulting mixture is refluxed for two hours,

cooled, diluted to 600 cc. with water and made alkaline with ammonium hydroxide. The precipitated product is removed by filtration, washed well with water and allowed to dry in the air.

A mixture consisting of 10 g. of 4-(4'-hydroxyanilino) -6-methoxyquinoline dissolved in absolute ethanol is treated with a solution of 3.2 g. of piperidlne and 1.2 g. of formaldehyde in cc. of absolute ethanol. The reaction mixture is heated under reflux for four hours, evaporated to onehalf volume and the warm solution treated with an excess of hydrogen chloride in absolute ethanol. Acetone is added until the solution becomesturbid and then the solution is cooled. The crude hydrochloride is recrystallized from the absolute ethanol-ethyl acetate mixture; M. P. 270 C. dec.

' Example 10.-4 (3'-N-pyrrolidylmethyl-4'-hydroxylanilino) -6-meth0:cyquinoline CHzCH:

HzN

Example 11 .4- (2'-hydroa:y-3'-diethylaminoethyl-5'-chloroanilino) -6-methoxyquinoline OH CH3N(CZH5)2 CHaO 471 14.5 g. of 2-hydroxy-5-chloroaniline is dissolved in 500 cc. of 95% ethanol and 6 cc. of concentrated hydrochloric acid. 19.4 g. of 4-choloro-6- methoxyquinoline is added and the mixture refluxed for three hours, evaporated to dryness and g the residue treated with 700 cc. of water. The

4- (2'-hydroxy-5'-chloroanilino -6-methoxyquinoline is precipitated by the addition of ammonium hydroxide, collected. washed with water and dried.

15 g. of 4-(2'-hydroxy-5'-chloroanilino)-6- methoxyquinoline is added to a solution of 1.8 g. of paraformaldehyde and 4.1 g. of diethylamine in 500 cc. of methanol and the resulting mixture refluxed for twenty-four hours. The mixture is made alkaline with ammonium hydroxide, evaporated to dryness and the residue treated with 300 cc. of water. The free base is extracted with ether, the ether extract dried and the dried extract treated with an excess of dry hydrogen chloride. The precipitated dihydrochloride is collected and purified by recrystallization from absolute methanol; M. P. 205 C. dec.

Example 12.-4- (3'-di-n-hez:ylaminomethyl-4'- hydroxyanilino) -6.7-dimethylquinoline 5.7 g. of p-aminophenol is dissolved in 300 cc. of water and cc. of dioxane and the pH of the solution adjusted to about 4 by the addition of concentrated hydrochloric acid. 19.1 g. of 4- chloro-6,'7-dimethylquinoline is added and the mixture refluxed for three hours. The solution is cooled, diluted with about 200 cc. of water and made alkaline with ammonium hydroxide. The precipitated 4-(-1'-hydroxyanilino) -6,7-dimethylquinoline is removed by filtration, washed well with water and allowed to dry in the air.

A solution of 1.8 g. of paraformaldehyde and 11 g. of di-n-hexylamine in 25 cc. of methanol is added to 13.2 g. of bit-hydroxyanilino)-6,7- dimethylquinoline in 400 cc. methanol. The mixture is refluxed for twenty-four hours, evaporated to about one-third'volume and treated with an excess of dry hydrogen chloride. Acetone is added and the precipitated hydrochloride removed by filtration and purified by recrystallization from absolute methanol-acetone mixture,

By using diethylamine in the above procedure 4-(3'-diethylaminomethyl 4' hydroxyanilino) 6,7-dimethylquinoline is obtained; M. P. (base) 215 C.

Example 13.-4-(3'-N-piperid1 lmethyl-4'-hydroxy-W-chloroanilino) -7-bromoquinoline 14.5 g. of 2-chloro-4-hydroxyaniline is dissolved in 300 cc. of water and 40 cc. 2 N hydrochloric acid. The pH oithe solution is adjusted to about 4 by the addition of 10 N sodium hydroxide solution and 28.7 g. of 4,7-dibromoquinoline and 100 cc. of dioxane are added. The resulting mixture is refluxed for four hours, cooled, diluted with about 300 cc. of water' and made alkaline with ammonium hydroxide. The 4-(2'-chloro-4-hydroxyanilino) -7-bromoquinoline, which separates, is removed by filtration, washed with water and allowed to dry in the air.

17.5 g. of 4-(2-chloro-4-hydroxyanilino) -7- bromoquinoline in 400 cc. of methyl is added to a solution of 1.7 g. of paraformaldehyde and g. of piperidine in 30 cc. of methanol and the mixture refluxed for twelve hours. The reaction mixture is evaporated to dryness, and the residue treated with 400 cc. of water and the mixture made alkaline with ammonium hydroxide. The base is extracted with chloroform, the chloroform extractsdried and treated with an excess of dry hydrogen chloride. The gummy dihydrochloride which separates is collected and recrystallized from methanol.

Example 1d.--d- (2'-hromo-d' diethylaminomethyl-5 mydroacydnilino) -?-cyanoquinoline ommcmomh resulting mixture refluxed for twelve hours. The

mixture is evaporated to one-half volume, treated with an excess of dry hydrogen chloride and the dihydrochloride salt precipitated hy the addition of acetone. The rude dlhydrochloride is purified by recrystallization from absolute methanol.

Example 15.-4i- (3' -diethylamimmethyE-d' hydroxyanilino) -5-chloro-t-methoryquinoline Cl NH-QOH on; 11.5 g. of p-aminophenol is dissolved in 509 cc. of water and the p11 of the solution adjusted to about t by the addition oi sulfuric acid. 22.8 g. of 4,5-dichloro-B-methoxyquinollne is added and the mixture refluxed for four hours, cooled, and

made alkaline with ammonium hydroxide. The precipitated 4-(ehydroxyanilino) -5-chloro-9- methoxyquinollne is removed by filtration, washed with water and dried.

A solution of 1.8 g. or paraformaldehyde and 4.4 g. of diethylamine in 25 cc. methanol is added to a solution of 15 g. of 4-(e'-anilino-5-chloro- 8-methoxyquinoline in methanol and resulting mixture refluxed for sixteen hours. The reaction mixture is concentrated to about one-half volume, an excess'of dry hydrogen chloride gas added and the dihydrochloride precipitated by the addition of acetone. The crude dihydrochloride is purified by recrystallization from methanol acetone mixture; M. P. 230-31 (3. dec. 9 v

The 4-haloquinolines used as starting materials can be prepared by the method of Magidson and Rubstov [3. Gen. Chem. (U. S. S. 3.), 'l, 1896 The mixture is (1937) C. A., 32, 564 (1938)] or from the corresponding hydroxyquinolines which may be prepared by the method of Gould and Jacobs [5. Am. Chem. Soc., 61, 2890 (1939)] or Iby that of Theos J. Thompson [M. S. Thesis, University of Nebraska, July 24 (1942)]. The 3-substituted-4- hydroxyquinolines are prepared by the method given in U. S, Patent No. 2,233,970.

Attention is directed to our copending applications Serial No. 556,496, filed Sept. 29, 1944; Serial No. 576,900, filed Feb. 8, 1945; and Serial Nos. 626,907 and 626,908, both filed on Nov. 5, 1945, wherein we have disclosed and claimed certain of the quinoline compounds which may be produced by the process claimed in the instant case.

What we claim as our invention is:

1. Process for obtaining a compound of the formula,

which comprises reactingan aminophenol having at least one unsubstituted position ortho and para to the phenolic hydroxyl radical with a d-halo quinoline compound of the formula,

thereby forming hydrogen halide and a 4-(hydroxyanilino) quinoline compound of the formula,

and thereafter condensing said d-(hydroxyaniline) qulnoline with a reactant of the group consisting of a mixture ofiormaldehyde and an amine of the formula.

/Ri HN and equivalent reaction products resulting from first condensing said amine and formaldehyde, thereby introducing the group into the aryl nucleus in one of the positions ortho and para with respect to the phenolic hydroxyl radical present in said nucleus, where X is a member of the class consisting of chlorine and bromine, Z is a member of the class consisting of hydrogen, halogen, CN, lower alkyl and lower alkoxy, n is one of the integers consisting of one and two, R is a member of the class consisting of hydrogen, halogen, --OH, and lower alkenyhRr is a member of the class consisting of hydrogen and alkyl radicals of 1 to 10 carbon 7 atoms inclusive, R: is a member of the class consisting of alkyl radicals of 1 tom carbon atoms,

inclusive and further members in which R11 and R2 taken together with +N forms a heteroeyclic ring containing not more than fire carbon atoms. 2. Process for obtaining a compound of the formula, a, on

NH In m ----CH|N J 2,

which comprises reacting an aminophenol having at least one unsubstituted position ortho and,

para to the phenolic hydroxyl radical with a 4-! haloquinoline compound of the formula, V

in the presence of acids'thereby' forminghydrogen halide and a 4-(hydroxyanillno) quinoline compound of the formula,

2. F L N and thereafter condensing said a-(hydroxyanilino) quinoline with a reactant of the group consisting of a mixture of formaldehyde amine of the formula,

and equivalent reaction products resulting from first condensing said amine and formaldehyde, thereby introducing the group into the aryl nucleus in one of the positions ortho and para with respect to the phenolic hydroxyl radical present in said nucleus, where X is a and an member of the class consisting of chlorine and 1 bromine, Z is a, member of the class consisting of hydrogen, halogen, CN, lower alkyl and lower alkoxy, n is one of the integers consisting of one and two, R is a member of the class consisting of hydrogen, halogen, -OH, and lower alkenyl, R1, is:

a member of the class consisting of hydrogen and alkyl radicals of 1 to 10 carbon atoms inclusive, R2 is a member of the class consisting of alkyl radicals of 1 to 10 carbon atoms inclusive and further members in which R1 and R2 taken together with -N form of a heterocyclic ring con- 7 taining not more than five carbon atoms.

3. Process for obtaining a compound of theformula,

which comprises reacting an aminophenol having at least one unsubstituted position ortho and para to the phenolic hydroxyl rali'c'al with a 4- haloquinoline compound of the formula,

in the presence of a dilute mineral acid thereby forming hydrogen 'halide and a 4-(hydroxyanilino) quinoline compound of the formula,

YL J consisting of a mixture of formaldehyde and an amine of the formula,

/Ri HN\Y J I Bi:

and equivalent reaction products resulting from first condensing said amine and formaldehyde, therby introducing the group -CH2N R, into the aryl nucleus in one of the positions ortho and para with respect to the phenolic hydroxyl radical present in said nucleus, where X is a member of the class consisting of chlorine and bromine, Z is a memberof the class consist-- ing of hydrogen, halogen, 'CN, lower alkyl and lower alkoxy, n is one of the 'integers consisting of one and two, R is a member of the class consisting of hydrogen, halogen, OH, and lower alkenyl, R1 is a member of the class consisting of hydrogen and alkyl radicals of 1 to 10 carbon atoms inclusive,-R-.- is a member of the class *consisting of alkyl radicals of 1 to 10 carbon atoms inclusive and further members in which R1 and R2 taken together with N -form of heterocyclic ring containing not more than five carbon atoms.

4. Process for obtaining. a compound of the arc-men which comprises reacting p-aminophenol with a 4-haloquinoline compound of the formula,

thereby forming hydrogen halide and a 4-(hydroxyanilino)-quinoline compound of the formula,

N and thereafter condensing said 4-(hydroxyaniiino) quinoline with a reactant of the group consisting of a mixture of formaldehyde and diethylamine and equivalent reaction products resulting from first condensing diethylamine and formaldehyde, thereby introducing the group CHzN(CHzCI-Is)z into. the aryl nucleus, where X is a member of the class consisting of chlorine and bromine. I

5. Process for obtaining a compound of the formula,

013x03: H|N on, Q N CHIC which comprises reacting p-aminophenol with a 4-haloquinoline compound of the formula,

thereby forming hydrogen halide and a 4-(hydroxyaniiino) -quinoline compound of the formula,

and thereafter condensing said i-(hydroxyanilino) quinoline with a reactant of the roup consisting of a mixture of formaldehyde and piperidine and equivalent reaction products resuiting from first condensing piperidine and formaldehyde, thereby introducing the group CHICK:

into the aryl nucleus, where X is a member of the class consisting of chlorine and bromine.

6. Process for obtaining a compound of the formula,

arr-Q03 mmcnicmcmcrma which mmprises reacting p-aminophenol with a i-haloquinoline compound of the formula.

thereby forming hydrogen halide and a 4 -(hydroxyanilino) quinoline compound of the formula,

and thereafter condensing said 4-(hydroxyanilino) quinoline with a reactant of the group consisting of a mixture of formaldehyde and din-butylamine and equivalent reaction products resulting from first condensing di-n-butylamine and formaldehyde, thereby introducing the group --CH2N(CH 2CHzCHaCI-Ia)z into the aryl sisting of chlorine and bromine.

7. A compound or the class consisting of a free base and'its acid, addition salts, said free base having the formula,

BIN

Halogen R2 85 N/ where R1 is a member of the class consisting of hydrogen and alkyl radicals of 1 to 10 carbon atoms inclusive, R: is a member of the class consisting of alkyl radicals of 1 to 10 carbon atoms inclusive and further members in which R1 and R: taken together with --N form a heterocyclic ring containing not more than five carbon atoms.

8. A compound of the formula,

NHQOH OHQUHI anoi 9. A compound of the formula.

NH OH to cmcmcmon.

N, \CHQOHQOHIOKI JOSEPH H. BURCKHALTER. ELDON M. JONES. ALBERT L. RAWLINS. FRANK H. TENDICK. WALTER F. HOIBOMB.

sameness crrnn The following references are of record in the iile of this patent:

rmrrnn s'ra'rns ra'rnu'rs Number Name Date 1,891,980 Hartmann Dec. 27, 1932 1,a9s,4c1 Muth Feb. '1, 19s: Bchonhofer Mar. 21, 19:8

nucleus, where X is a member of the class con- 

